Lab History

The group was started in 1982 when John moved from London to join the faculty at Stanford. Initially, we put our major effort into studying the causative agent of African Sleeping Sickness, Trypanosoma brucei. Over a period of about 15 years, we made many interesting discoveries about the fundamental molecular biology of this parasite including co-discovery of RNA trans-splicing and polycistronic transcription. Once these novel processes were uncovered we put much effort into understanding the machinery involved and the consequences to the parasite’s overall biology. One example of the latter is their reliance on RNA turnover rather than regulated transcription as a means of modulating transcript abundance in development. Our trypanosome work ended in about 1997 when John decided that, much as these parasites are incredibly interesting from a molecular biology viewpoint and important as pathogens, the lab’s work on them was moving further and further from their fundamental biology. Simultaneously, the lab was moving deeper and deeper into the study of another parasite where the biology was remaining front and center and so the decision was made (reluctantly but, even in hind-sight, correctly) to consolidate the entire lab’s effort on Toxoplasma.

We actually began work on Toxoplasma in 1983. Entry into this field was motivated by the sense that trypanosomes, as the first parasites to be really attacked with molecular biology, had proven to be a gold mine of amazingly interesting, novel biology. What, then, might some of the other, completely unexplored parasites hold in store for us? There was also the sense that the trypanosome field was rapidly becoming full of way too much talent and while competition is fun and motivating, it’s nice to think that if Palo Alto went down in “the big one” (a major earthquake), there might be some consequence other than only two labs would make some important, new discovery instead of the usual three (which was rapidly becoming the pattern). And, lastly, trypanosomes, for all their wonders, lacked some biology that we were really itching to study. So, with all this in mind, John set out to find a parasite system that met several criteria where trypanosomes came up short. Specifically, he went looking for a system that was:

an intracellular parasite (what could be cooler than one eukaryotic cell getting into and taking over the workings of another such cell?!?)

genetically tractable (classical “forward” genetics is an amazingly powerful tool that, to that point, had not been much exploited in Parasitology (with a few very notable exceptions!)).

clinically important (when the experiments aren’t working, it’s nice to know that there is a higher purpose to the work).

easy to handle in the lab (parasites can be tough systems to study because the animal models are complex and expensive and/or they can’t be grown in vitro).

relatively unexplored from the molecular biology standpoint (it’s nice to work on a system where there is already a lot of good work but in areas complementary to one’s own expertise).

Toxoplasma met all of these criteria and then some. Specifically, it has a haploid genome (obtaining mutants is much easier as a result); it can be easily grown in almost any cell type; it has (and had, even then) a well-described life cycle with full classical genetics (as beautifully established by Elmer Pfefferkorn and colleagues); it is an important pathogen of both animals and people; and it forms plaques in tissue culture monolayers making it possible to handle and study it more or less the way you would a big virus (which appealed to John’s background in virology). But most importantly, there were already some great individuals working on everything but the molecular biology including the aforementioned Elmer Pfefferkorn, Stanford’s own Jack Remington and the Toxo twins at Dartmouth, Lloyd Kasper and Joe Schwartzman. Lloyd was the one who really sold John on the system and provided all the materials to get our lab up and running with the system.